• Event-free survival 3 years after completion of study treatment [ Designated as safety issue: No ]
  
• Prosthesis survival as assessed by prosthesis failure when surgery is required [ Designated as safety issue: No ]
  

• Safety and toxicity as assessed by creatinine and creatinine clearance monthly prior to each course and for 1 year after completion of study treatment [ Designated as safety issue: Yes ]
  
• Tumor necrosis as assessed by the Huvos grading system 12 weeks after beginning treatment, at time of definitive surgery after induction chemotherapy [ Designated as safety issue: No ]
  
• Radiographic response as assessed by RECIST criteria 10 weeks after beginning treatment, after induction chemotherapy, and before definitive surgery [ Designated as safety issue: No ]
  
• Correlate biological studies with clinical outcome as assessed by protocol 97-094 "Chemotherapy Resistance in Osteogenic Sarcoma) at diagnosis [ Designated as safety issue: No ]
  

OBJECTIVES:

• Determine the safety and feasibility of pamidronate with standard induction and maintenance chemotherapy in patients with newly diagnosed high-grade osteosarcoma.
• Determine the frequency of favorable tumor necrosis produced in patients treated with this regimen.
• Determine the event-free survival of patients without metastatic disease at presentation treated with this regimen.
• Determine the prosthesis failure-free survival of patients treated with this regimen and who ultimately undergo limb preservation surgery with insertion of an endoprosthesis.

OUTLINE: Patients are stratified according to extent of disease (localized vs metastatic).

• Induction therapy: Patients receive standard chemotherapy comprising cisplatin IV over 4 hours and doxorubicin IV over 15-30 minutes on weeks 0 and 5 and high-dose methotrexate IV over 4 hours on weeks 3, 4, 8, and 9. Patients also receive pamidronate IV over 2-4 hours beginning approximately 3 days after initiation of chemotherapy on week 0 and repeating once every 4 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
• Surgery*: Patients undergo surgical resection of primary tumor on week 10 and then proceed to maintenance therapy. Patients with metastatic disease undergo further surgery of metastatic sites after recovery from definitive resection of the primary tumor before proceeding to maintenance therapy.

NOTE: *Patients who have undergone definitive surgical resection before study entry may proceed to maintenance therapy or, if appropriate, surgical resection of metastatic disease

• Maintenance therapy: Patients receive standard chemotherapy comprising cisplatin IV over 4 hours on weeks 0 and 5; doxorubicin IV over 15-30 minutes on weeks 0, 5, 10, and 15; and high-dose methotrexate IV over 4 hours on weeks 3, 4, 8, 9, 13, 14, 18, and 19. Patients also receive pamidronate as in induction therapy for up to 1 year. Treatment continues in the absence of disease progression or unacceptable toxicity.

Patients are followed monthly for 1 year.

PROJECTED ACCRUAL: A total of 75 patients (50 with localized disease; 25 with metastatic disease) will be accrued for this study within 3-4 years.